Many solutions prepared from one or more solid substances (in the following referred to as ‘a solid substance’) and one or more liquid solvents (in the following referred to as ‘a liquid solvent’) are not sufficiently stable for being stored over an extended period of time. For example, this holds for certain solutions to be injected into a patient, such solutions containing one or more active pharmaceutical ingredients (in the following referred to as ‘an active pharmaceutical ingredient’), but is of course not limited to this field of application. An active pharmaceutical ingredient is a substance in a drug that is biologically active. For example the active pharmaceutical ingredient causes the direct effect on the disease diagnosis, prevention, treatment or cure, and may comprise one or more proteins, antibodies, small molecules, etc. The active pharmaceutical ingredient may be provided as a soluble solid substance. This soluble solid substance may or may not contain additional excipients, and can be stably stored over extended periods of time. When the time has come to administer the active pharmaceutical substance, it is then to be solved in the liquid solvent (e.g. water for injection, saline solution or another liquid solvent for injection which may or may not contain an additional active pharmaceutical ingredient in order to yield the definitive solution before administering, e.g. injecting, infusing etc. to the patient.
The solid substances comprising the active pharmaceutical ingredient are often obtained through lyophilisation. Other common ways to obtain solid substances are spray drying and other drying processes known in the art. Lyophilization is often used because it is a gentle process of obtaining the solid substance containing the active pharmaceutical ingredient. Solid substances obtained through lyophilisation can be stably stored in a container in the form of powder or granules, or in the form of a compact cake, and are typically soluble in the liquid solvent (e.g. water for injection, saline, or other diluents). Accordingly, due to the solubility of the lyophilised solid substance comprising the active pharmaceutical ingredient, the solution to be administered to the patient can be easily obtained by completely solving the lyophilized soluble solid substance in the liquid solvent, for example water for injection. The solution obtained in this manner is commonly referred to as a ‘reconstituted solution’.
Regulatory frameworks require that a solution to be injected into a patient is free of visible particles. In other words, the solid substance must be visually completely dissolved in the liquid solvent before the solution is allowed to be injected into the patient. Any administration of solid material needs to be avoided. Regulatory frameworks additionally require that reconstitution of the solution to be injected is performed in the primary packaging container, which may be, for instance, a vial, a syringe (e.g. a dual chamber syringe), or an ampoule. Reconstitution can also in certain cases be performed in other relevant containers. Additionally, lyophilized powder or cake may be dissolved for further processing and not for final administration to patients. Examples include freeze-drying of active ingredient with or without additional excipients. Final dissolution of the solid material is also expected and required in that case.
Accordingly, the instructions provided by the manufacturer providing the predetermined amount of the solid substance containing the active pharmaceutical ingredient include the predetermined amount and type of the liquid solvent (e.g. water for injection) to be used in case the liquid solvent is not provided by the manufacturer itself together with the solid substance containing the active pharmaceutical ingredient. In addition, these instructions include the so-called ‘reconstitution time’. The reconstitution time is the duration between the time of starting to solve the predetermined amount of the solid substance in the predetermined amount of the liquid solvent and the time reconstitution of the solution is completed, so that the solution has formed the reconstituted solution which does not contain any undissolved material.
Additional instructions may be provided for the preparation of the reconstituted solution, such as the temperature of the solid substance and/or the temperature of the liquid solvent and/or the temperature of the container in which the reconstituted solution must be prepared, as well as instructions related to a movement pattern of the container during solving the solid substance in the liquid solvent (e.g. a movement pattern comprising time intervals during which the container must be shaken, interrupted by time intervals in which the container is not moved).
To be able to provide these instructions, it must be determined when reconstitution of a solution is completed to allow for determination of the reconstitution time. This is presently performed by human individuals through visual inspection of the solution prepared by solving the predetermined amount of the solid substance in the predetermined amount of the liquid solvent (e.g. water for injection) in the container with a given and defined reconstitution procedure. This usually means that a plurality of individuals determine the duration between the time of starting to solve the predetermined amount of the solid substance in the predetermined amount of liquid solvent until the time there are no undissolved visible solid materials or particles contained in the reconstituted solution anymore. As is evident, this is greatly influenced by the individual visual perception of the humans and, consequently, different humans may come to very different results as regards the reconstitution time.
As mentioned, the manufacturer of the active pharmaceutical ingredient typically specifies the reconstitution time (and potentially other relevant parameters, see above) in the instructions provided together with the active pharmaceutical ingredient. To be on the safe side, the manufacturer—taking the different reconstitution times determined by the human individuals into account—must specify in the instructions (besides potential other relevant parameters) a reconstitution or holding time which is sufficiently long to make sure that indeed reconstitution of the solution is completed after the reconstitution time, so that there are no undissolved visible solid particles contained in the solution anymore. For lyophilized products containing significant amount of solid and protein, this reconstitution procedure can take up to 15 to 40 minutes.